Investigations which have characterized the nature of cellular dysfunction in shock have led to major improvements in early care of the septic and injured patient. Initial resuscitation is well developed, and has led not only to adequate therapy for the routine injury, but also to increasing salvage of the most severely injured. The underlying mechanisms of cell derangement appear to be mediated in part by the host response. These alterations must be better defined to allow more specific interventions which may lead to improved therapy. A variety of endogenous substances have recently been characterized as potential mediators of various shock states, including eicosanoids, platelet activating factor, and monochines, particularly cachectin. Ongoing development of precise pharmacologic modulators, including synthesis inhibitors and receptor antagonists and agonists, when employed in appropriate models, allow assessment of the biologic significance of these host products in shock. The central hypothesis is that mediator- induced early cell dysfunction, measured by in vivo transmembrane potential changes, is a primary event, rather than secondary to measured changes in cellular energetics (by in vivo nuclear magnetic resonance 31P spectroscopy), permeability (by freeze-clamp tissue biopsy analysis), or flow redistribution (by hepatic galactose elimination kinetics and radiolabeled microspheres). Host mediators, which developed as initial adaptive responses to severe injury, may now have maladaptive deleterious consequences in the evolutionarily brief setting of the resuscitated patient. Cell level evaluation of the variety of effects of these substances should eventually allow specific control of only the injurious component of the necessary humoral host responses.